immuno chapter 5


Cell-Mediated Immune Responses

Cell-mediated immunity combats infections by intracellular microbes; mediated by T lymphocytes

Elimination of microbes able to live in phagocytic vesicles or in cytoplasm of infected cells is main function of T cell arm of adaptive immunity

To perform their functions, T lymphocytes have to interact with other cells, which may be phagocytes, infected host cells, or B lymphocytes o Specificity of T cells for peptides displayed by MHC molecules ensures they see and respond only to antigens associated with other cells

Phases of T Cell Responses

Naïve T lymphocytes constantly recirculate through peripheral lymphoid organs searching for foreign protein antigens; naïve T cells express antigen receptors and other molecules that make up machinery of antigen recognition, but naïve lymphocytes incapable of performing effector functions required for eliminating microbes o Naïve T cells have to differentiate into effector cells; initiated by antigen recognition o Protein antigens of microbes transported from portals of entry of microbes to same peripheral lymphoid organs through which naïve T cells recirculate; there antigens processed and displayed by MHC molecules on dendritic cells o Naïve T cells enter lymph nodes from circulation, and then rapidly move around in nodes, scanning surfaces of dendritic cells for presence of antigen o When T cell recognizes antigen, cell transiently stops moving and initiates activation program o At same time as T cells are seeing antigen, they receive additional signals in form of microbial products or molecules expressed by APCs during innate immune reactions to microbes

On activation by antigen and other stimuli, antigen-specific T cells begin to secrete cytokines o Some cytokines stimulate proliferation of antigen-specific T cells, resulting in rapid increase in number of antigen-specific lymphocytes (clonal expansion) o Fraction of activate lymphocytes undergo differentiation, which results in conversion of naïve T cells into population of effector T cells to eliminate microbes o Some effector T cells may remain in lymph node, where they function to eradicate infected cells in lymph node or provide signals to B cells that promote antibody responses against microbes o Other effector T cells leave lymphoid organs where they differentiated from naïve T cells, enter circulation, and migrate to any site of infection, where they eradicate infection o Some of progeny of T cells that have proliferated in response to antigen develop into memory T cells

(long-lived and functionally inactive and circulate for months or years, ready to rapidly respond to repeat exposures to same microbe) o As effector T cells eliminate infectious agent, stimuli that triggered T cell expansion and differentiation also eliminated; as result, greatly expanded clone of antigen-specific lymphocytes dies, thereby returning system to basal resting state

Antigen Recognition and Costimulation

Initiation of T cell responses requires multiple receptors on T cells recognizing ligands on APCs; TCR recognizes

MHC-associated peptide antigens, CD4 or CD8 coreceptors recognize MHC molecules, adhesion molecules strengthen binding of T cells to APCs, and receptors for costimulators recognize second signals provided by APCs o Molecules other than antigen receptors involved in T cell responses to antigens called accessory molecules of T lymphocytes; accessory molecules invariant among all T cells

 Accessory molecules involved in signaling and adhesion

 Different accessory molecules bind to different ligands and each interaction plays distinct and complementary role in process of T cell activation

TCR and CD4 or CD8 coreceptor together recognize complex of peptide antigens and MHC molecules on APCs, and this recognition provides first or initiating signal for T cell activation o When protein antigens are ingested by APCs from extracellular milieu into vesicles, these antigens processed into peptides that are displayed by class II MHC molecules o Protein antigens present in cytoplasm processed into peptides that are displayed by class I MHC molecules o TCR of peptide antigen-specific T cell recognizes displayed peptide and simultaneously recognizes residues of MHC molecule that are located around peptide-biding cleft

o CD4 or CD8 function with TCR to bind MHC molecules o At time when TCR is recognizing peptide-MHC complex, CD4 or CD8 recognizes class II or class I MHC molecule at site separate from peptide-binding cleft

 CD4+ T cells (function as cytokine-producing helper cells) recognize microbial antigens ingested from extracellular milieu and are displayed by class II MHC molecules

 CD8+ T cells (function as CTLs) recognize peptides derived from cytoplasmic microbes displayed by class I MHC molecules

 Specificity of CD4 and CD8 for different classes of MHC molecules and distinct pathways of processing of vesicular and cytosolic antigens ensure correct T cells respond to different microbes

 2+ TCRs and coreceptors need to be engaged simultaneously to initiate T cell response because only if multiple TCRs and coreceptors are brought together can appropriate biochemical signaling cascades be activated

 Only one T cell can respond only if it encounters array of peptide-MHC complexes on APC

 Each T cell needs to engage antigen (i.e., MHC-peptide complexes) for long period (at least several minutes) or multiple times to generate enough biochemical signals to initiate response; then T cell begins activation program o Biochemical signals that lead to T cell activation triggered by set of proteins that are linked to TCR to form TCR complex and by CD4 or CD8 coreceptor

 Different T cells must possess antigen receptors that are variable enough to recognize diverse antigens and other molecules that serve conserved signaling roles and don’t need to be variable

 TCR recognizes antigens, but not able to transmit biochemical signals to interior of cell; TCR noncovalently associated with complex of 3 proteins (CD3) and homodimer of signaling protein

(ζ chain); TCR, CD3, and ζ chain make up TCR complex

 In TCR complex, function of antigen recognition performed by variable TCR α and β chains, whereas conserved signaling function performed by attached CD3 and ζ proteins o T cells can be activated experimentally by molecules that bind to TCRs of many or all clones of T cels, regardless of peptide-MHC specificity of TCR; polyclonal activators include antibodies specific for TCR or associated CD3 proteins, polymeric carb-binding proteins (such as phytohemagglutinin), and certain microbial proteins (superantigens)

 Polyclonal activators often used as experimental tools to study T cell responses and in clinical settings to test for T cell function or prepare metaphase spreads for chromosomal analysis

 Microbial superantigens may cause serious disease by inducing excessive cytokine release from many T cells

Adhesion molecules on T cells recognize their ligands on APCs and stabilize binding of T cells to APCs o Most TCRs bind peptide-MHC complexes for which they are specific with low affinity

 T cells positively selected for weak recognition of self antigens and ability to recognize foreign microbial peptides is fortuitous and not predetermined o To induce productive response, binding of T cells to APCs must be stabilized for sufficiently long period that necessary signaling threshold is achieved

 Stabilization function performed by adhesion molecules on T cells whose ligands are expressed on APCs; most important are integrins

 Major T cell integrin involved in binding to APCs is LFA-1 (leukocyte function-associated antigen), whose ligand on APCs is ICAM-1 (intercellular adhesion molecule) o Integrins play important role in enhancing T cell responses to microbial antigens

 On resting naïve T cells, LFA-1 integrin in low-affinity state; if T cell exposed to chemokines produced as part of innate immune response to infection, that T cell’s LFA-1 molecules converted to high-affinity state and cluster together in minutes so T cells bind strongly to APCs

 Antigen recognition by T cell increases affinity of that cell’s LFA-1; once T cell sees antigen, it increases strength of its binding to APC presenting that antigen, providing positive feedback loop

 Integrins also play important role in directing migration of effector T cells from circulation to sites of infection

Full activation of T cells dependent on recognition of costimulators (second signals) on APCs o Best-defined costimulators for T cells are B7-1 (CD80) and B7-2 (CD86), both of which expressed on APCs and whose expression greatly increased when APC encounters microbes

 B7 proteins recognized by receptor (CD28) expressed on virtually all T cells

 Signals from CD28 on T cells binding to B7 on APCs work together with signals generated by binding of TCR and coreceptor to peptide-MHC complexes on same APCs

 CD28-mediated signaling essential for initiating responses of naïve T cells; in absence of Cd28-B7 interactions, engagement of TCR alone unable to activate T cells o Requirement for costimulation ensures that naïve T lymphocytes activated fully by microbial antigens, and not by harmless foreign substances because microbes stimulate expression of B7 costimulators o CD40 ligand (CD154) on T cells and CD40 on APCs – don’t directly enhance T cell activation; CD40L expressed on antigen-stimulated T cell binds to CD40 on APCs and activates APCs to express more B7 costimulators and secrete cytokines (such as IL-12) that enhance T cell differentiation

 CD40L-CD40 interaction promotes T cell activation by making APCs better at stimulating T cells o Protein antigens, such as those used in vaccines, fail to elicit T cell-dependent immune responses unless these antigens administered with substances that activate APCs, including dendritic cells and macrophages (possible B cells); these called adjuvants and function mainly by inducing expression of costimulators on APCs and stimulating APCs to secrete cytokines that activate T cells

 Most adjuvants products of microbes (e.g., killed mycobacteria) or substances that mimic microbes; adjuvants convert inert protein antigens into mimics of pathogenic microbes

Enhancing expression of costimulators may be useful for stimulating T cell responses (e.g., against tumors), and blocking costimulators may be strategy for inhibiting unwanted responses o Agents that block B7:CD28 used in treatment of RA and other inflammatory diseases o Antibodies that block CD40:CD40L interactions being tested in inflammatory diseases and transplant recipients to reduce or prevent graft rejection

Proteins homologous to CD28 critical for limiting and terminating immune responses o Different members of CD28 family involved in activating and inhibiting T cells o CTLA-4 recognize B7 on APCs; involved in inhibiting responses to some tumors o PD-1 recognizes different but related ligands on many cell types; inhibits responses to some infections and allows infections to become chronic o Both CTLA-4 and PD-1 induced in activated T cells, and genetic deletion of molecules results in excessive lymphocyte expansion and autoimmune disease

Activation of CD8+ T cells stimulated by recognition of class I MHC-associated peptides and requires costimulation and/or helper T cells o Initiation of activation of CD8+ T cells often requires that cytoplasmic antigen from one cell has to be cross-presented by dendritic cells o Differentiation into CTLs may require concomitant activation of CD4+ helper T cells

 When virus-infected cells ingested by host dendritic cells and viral antigens cross-presented by

APCs, same APC may present antigens from cytosol in complexes with class I MHC molecules and from vesicles in complex with class II MHC molecules

 Both CD8+ T cells and CD4+ T cells specific for viral antigens activated near one another

 CD4+ T cells may produce cytokines or membrane molecules that help activate CD8+ T cells

 Requirement for helper T cells in CD8+ T cell responses likely explanation for defective CTL responses to many viruses in patients infected with HIV, which kills CD4+ but not CD8+ cells o CTL responses to some viruses don’t appear to require help from CD4+ T cells

Biochemical Pathways of T Cell Activation

On recognition of antigens and costimulators, T cells express proteins involved in proliferation, differentiation, and effector functions of cells o Naïve T cells that haven’t encountered antigen (resting cells) have low level of protein synthesis o Within minutes of antigen recognition, new gene transcription and protein synthesis seen in activated T

 cells

Biochemical pathways that link antigen recognition with T cell responses consist of activation of enzymes, recruitment of adaptor proteins, and production of active transcription factors

o Biochemical pathways initiated by physically bringing together multiple TCRs (cross-linking) and they occur at or near TCR complexes o Multiple TCRs and coreceptors brought together when they bind MHC-peptide complexes that are near one another on surface of APCs o There is orderly redistribution of other proteins in both APC and T cell membranes at point of cell-to-cell contact, such that TCR complex, CD4/CD8 coreceptors, and CD28 coalesce to center and integrins move to form peripheral ring

 Responsible for optimal induction of activating signals in T cell o Immunologic synapse – region of contact between APC and T cell, including redistributed membrane proteins; may secrete some effector molecules and cytokines, ensuring they don’t diffuse away but are targeted to APC

 Enzymes that serve to degrade or inhibit signaling molecules recruited to synapse o Clustering of CD4 or CD8 coreceptors activates tyrosine kinase (Lck) that is noncovalently attached to cytoplasmic tails of coreceptors

 Several transmembrane signaling proteins associated with TCR, including CD3 and ζ chains, which both contain tyrosine-rich motifs (immunoreceptor tyrosine-based activation motifs or

ITAMs) critical for signaling

 Lck carried near TCR complex by CD4 or CD8 molecules; phosphorylates tyrosine residues contained within ITAMs of ζ and CD3 proteins

 Phosphorylated ITAMs of ζ chain become docking sites for tyrosine kinase (ZAP-70) which also is phosphorylated by Lck and thereby made enzymatically active

 Active ZAP-70 phosphorylates various adapter proteins and enzymes, which assemble near TCR complex and mediate additional signaling events

 Major signaling pathways linked to ζ chain phosphorylation and ZAP-70 are calcium-NFAT pathway, Ras/Rac-MAP kinase pathway, and PKCθ-NF-κB pathway

Nuclear factor of activated T cells (NFAT) – transcription factor whose activation is dependent on Ca 2+ ; calcium-

NFAT pathway initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ), which catalyzes hydrolysis of PM inositol phospholipid (phosphatidylinositol 4,5-bisphosphate or PIP


) o One byproduct of PLCγ-mediated PIP


breakdown (inositol 1,4,5-trisphosphate or IP


) stimulates release of Ca 2+ from ER, thereby raising cytoplasmic Ca 2+ concentration o In response to elevated Ca 2+ , PM calcium channel opens, leading to influx of extracellular Ca 2+ into cell, which sustains elevated Ca 2+ for hours o Cytoplasmic Ca 2+ binds to calmodulin; Ca 2+ -calmodulin complex activates phosphatase (calcineurin), which removes phosphates from NFAT, which resides in cytoplasm

 Once dephosphorylated, NFAT able to migrate into nucleus, where it binds to and activates promoters of several genes, including genes encoding T cell growth factor IL-2 and components of IL-2 receptor

 Cyclosporine binds to and inhibits activity of calcineurin and thus inhibits production of cytokines by T cells; widely used as immunosuppressive drug to prevent graft rejection

Ras/Rac-MAP kinase pathways include GTP binding Ras and Rac proteins, several adaptor proteins, and cascade

 of enzymes that eventually activate one of family of MAP (mitogen-activated protein) kinases o Pathways initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at PM, leading to recruitment of Ras or Rac, and their activation by exchange of bound GDP with GTP o Ras·GTP and Rac·GTP initiate different enzyme cascades, leading to activation of distinct MAP kinases o Terminal MAP kinases in pathways (extracellular signal-related kinase or ERK and c-Jun amino-terminal kinase or JNK) promote expression of protein (c-Fos) and phosphorylation of c-Jun o c-Fos and phosphorylated c-Jun combine to form transcription factor AP-1, which enhances transcription of several T cell genes

Third major pathway involved in TCR signaling consists of activation of θ isoform of serine-threonine kinase

(PKC) and activation of transcription factor NF-κB o PKC activated by diacylglycerol, which is generated by phospholipase C-mediated hydrolysis of membrane inositol lipids o PKCθ acts via adaptor proteins recruited to TCR complex to activate NF-κB

o NF-κB exists in cytoplasm of resting T cells in inactive form, bound to inhibitor called IκB o TCR-induced signals, downstream of PKCθ, activate kinase that phosphorylates IκB and targets it for destruction; as result, NF- κB released and moves to nucleus, where it promotes transcription of several genes

Fourth pathway involves lipid kinase phosphatidylinositol-3 (PI-3) kinase, which phosphorylates membrane PIP

2 to generate PIP

3 o PIP


ultimately activates serine-threonine kinase (Akt), which has many roles, including stimulating expression of anti-apoptotic proteins and thus promoting survival of antigen-stimulated T cells o PI-3 kinase/Akt pathway triggered by TCR, CD28, and IL-2 receptors

Various transcription factors (NFAT, AP-1, and NF-κB) stimulate transcription and subsequent production of cytokines, cytokine recpetors, cell cycle inducers, and effector molecules such as CD40L o All signals initiated by antigen recognition because binding of TCR and coreceptors to antigen (peptide-

MHC complexes) necessary to assemble signaling molecules and initiate enzymatic activity

Biochemical signals transduced by CD28 on binding to B7 costimulators less defined than TCR-triggered signals o Likely that CD28 engagement amplifies some TCR signals and initiates distinct set of signals that complement TCR signals

Functional Responses of T Lymphocytes to Antigen and Costimulation

Recognition of antigen and costimulators by T cells initiates orchestrated set of responses that culminate in expansion of antigen-specific clones of lymphocytes and differentiation of naïve T cells into effector cells and memory cells o Many of responses of T cells mediated by cytokines secreted by T cells and act on T cells themselves and on many other cells involved in immune defenses

In response to antigen and costimulators, T lymphocytes, especially CD4+ T cells, rapidly secrete several different cytokines that have diverse activities o Cytokines – large group of proteins that function as mediators of immunity and inflammation; secreted by T cells; different cytokines have distinct activities and play different roles in immune responses o First cytokine produced by CD4+ T cells (1-2 hours after activation) is IL-2

 Activation rapidly enhances ability of T cells to bind and respond to IL-2 by increasing expression of IL-2 receptor

 High-affinity receptor for IL-2 is 3-chain molecule

Naïve T cells express 2 signaling chains of receptor but don’t express the chain that enables receptor to bind IL-2 with high affinity

Within hours after activation by antigens and costimulators, T cells produce 3 rd chain of receptor and complete IL-2 receptor is able to bind IL-2 strongly

 IL-2 produced by antigen-stimulated T cells preferentially binds to and acts on same T cells; principal actions are stimulate survival and proliferation of T cells

Essential for maintenance of regulatory T cells and thus controlling immune responses

Stimulates T cells to enter cell cycle and begin to divide, resulting in increase in number of antigen-specific T cells o Differentiated effector CD4+ T cells produce many other cytokines o CD8+ T lymphocytes that recognize antigen and costimulators don’t secrete large amounts of IL-2, but they proliferate prodigiously during immune responses; possible that antigen recognition and costimulation able to drive proliferation of CD8+ T cells without requirement of IL-2

Within 1-2 days after activation, T lymphocytes begin to proliferate, resulting in expansion of antigen-specific clones; expansion helps adaptive immune response keep pace with rapidly dividing microbes and provides large pool of antigen-specific lymphocytes from which effector cells can be generated to combat infection o Before infection, frequency of CD8+ T cells specific for any one microbial protein antigen about 1 in 10 5 of 10 6 lymphocytes in body; at peak of some viral infections (may be within a week of infection) as many as 10-20% of all lymphocytes in lymphoid organs may be specific for that virus (increased 100,000x)

 Estimated doubling time is 6 hours o Enormous expansion of T cells specific for microbe not accompanied by detectable increase in bystander cells that don’t recognize that microbe

o Even in infections with complex microbes that contain many protein antigens, majority of expanded clones specific for only a few, and often less than 5, immunodominant peptides on that microbe o Expansion of CD4+ T cells only about 100-1000x o Many CTLs needed to kill large numbers of infected cells; each CD4+ effector cell secretes cytokines that activate many other effector cells, so relatively small number needed

Progeny of antigen-stimulated proliferating T cells begin to differentiate into effector cells; differentiation is result of changes in gene expression (e.g., activation of genes encoding cytokines or cytotoxic proteins) o Begins in concert with clonal expansion, and differentiated effector cells appear in 3-4 days of exposure to microbes o Differentiated effector cells leave peripheral lymphoid organs and migrate to site of infection, where they encounter microbial antigens that stimulated their development o On recognition of antigen, effector cells respond in their way

CD4+ helper T cells differentiate into effector cells that respond to antigen by producing surface molecules and cytokines that function to activate phagocytes and B lymphocytes o Most important cell surface protein is CD40L; gene transcribed in response to antigen recognition and costimulation, and result is CD40L expressed on helper T cells after activation

 CD40L binds to its CD40, which is expressed mainly on macrophages, B lymphocytes, and dendritic cells

 Engagement of CD40 activates these cells

 Interaction of CD40L on T cells with CD40 on dendritic cells stimulates expression of costimulators on APCs and production of T cell-activating cytokines, thus providing positive feedback (amplification) mechanism for APC-induced T cell activation

Helminthic parasites too large to be phagocytosed and immune response to helminths dominated by production of IgE antibodies and activation of eosinophils o IgE antibody binds to helminths, and eosinophils and other leukocytes destroy the helminthes

CD4+ helper T cells may differentiate into subsets of effector cells that produce distinct sets of cytokines and perform different functions o T


1 and T


2 cells distinguished by cytokines they produce and cytokine receptors and adhesion molecules they express o T


17 cells express cytokine IL-17 o Many activated CD4+ T cells produce various mixtures of cytokines and therefore can’t be readily classified into one of those subsets



1 cells stimulate phagocyte-mediated ingestion and killing of microbes; most important cytokine produced by



1 cells is interferon-γ (IFN-γ), which interferes with viral infection o IFN-γ is potent activator of macropahges (type I IFNs much more potent anti-viral cytokines than IFN-γ) o IFN-γ stimulates production of antibody isotypes that promote phagocytosis of microbes because antibodies bind directly to phagocyte Fc receptors, and they activate complement, generating products that bind to phagocyte complement receptors o IFN-γ also stimulates expression of class II MHC molecules and B7 costimulators on macrophages and dendritic cells; may serve to amplify T cell responses



2 cells stimulate phagocyte-independent, eosinophil-mediated immunity (especially effective against helminthic parasites) o T


2 cells produce IL-4 (stimulates production of IgE antibodies) and IL-5 (activates eosinophils) o IgE activates mast cells and binds to eosinophils; IgE-dependent mast cell-mediated and eosinophilmediated reactions important in killing helminthic parasites o Some cytokines produced by T


2 cells (IL-4 and IL-13) promote expulsion of parasites from mucosal organs and inhibit entry of microbes by stimulating mucus secretion

 Sometimes called barrier immunity because it blocks entry of microbes at mucosal barriers o Cytokines of T


2 cells also activate macrophages; T


2-mediated macrophage activation enhances synthesis of ECM proteins involved in tissue repair (alternative macrophage activation) o IL-4, IL-10, and IL-13 inhibit microbicidal activities of macrophages and thus suppress T


1 cell-mediated immunity; efficacy of cell-mediated immune responses against microbe determined by balance between activation of T


1 cells and T


2 cells



17 cells secrete cytokines IL-17 and IL-22 and are principal mediators of inflammation in number of immunologic reactions; implicated in MS, inflammatory bowel disease, and RA o Studies suggest T


17 cells also involved in defense against some bacterial and fungal infections

Development of T


1, T


2, and T


17 subsets regulated by stimuli that naïve CD4+ T cells receive when they encounter microbial antigens o T


1 differentiation driven by combination of IL-12 and IFN-γ

 In response to many bacteria and viruses, dendritic cells and macropahges produce IL-12 and NK cells produce IFN-γ

 When naïve T cells recognize antigens of these microbes, T cells also exposed to these cytokines, which activate transcription factors that promote differentiation of T cells to T


1 subset

 T


1 cells produce IFN-γ, which activates macrophages to kill microbes and promotes more T


1 development o Development of T


2 cells stimulated by IL-4; main source of IL-4 is T


2 cells

 If infectious microbe doesn’t elicit IL-12 production by APCs, T cells themselves produce IL-4

 Helminths may activate cells of mast cell lineage to secrete IL-4

 In antigen-stimulated T cells, IL-4 activates transcription factors that promote differentiation to



2 subset o Development and maintenance of T


17 cells require inflammatory cytokines such as IL-6 and IL-1

(produced by macrophages and dendritic cells), IL-23 (related to IL-12, made by same cells), and TGF-β o Once any of these populations develops from antigen-stimulated helper T cells, it produces cytokines that enhance differentiation of T cells toward its own subset and inhibits development of other populations (cross-regulation)

 May lead to increasing polarization of response toward one population

 Some differentiated CD4+ T cells can convert from one subset into another under certain conditions

CD8+ T lymphocytes activated by antigen and costimulators differentiate into CTLs able to kill infected cells expressing the antigen; effector CTLs secrete proteins that create pores in membranes of infected cells and induce DNA fragmentation and apoptotic death of these cells o Differentiation of naïve CD8+ T cells into effector CTLs accompanied by synthesis of molecules that kill infected cells

Fraction of antigen-activated T lymphocytes differentiate into long-lived memory cells; memory cells found in lymphoid organs, mucosal tissues, and circulation o Memory T cell require signals delivered by certain cytokines, including IL-7, in order to stay alive o Memory cells don’t continue to produce cytokines or kill infected cells, but may do so rapidly on encountering antigen they recognize o Subset of memory T cells (central memory cells) populate lymphoid organs and are responsible for rapid clonal expansion after re-exposure to antigen o Effector memory cells localize in mucosal tissue and mediate rapid effector functions on reintroduction of antigen to these sites

During immune response, survival and proliferation of T cells maintained by antigen, costimulatory signals from

CD28, and cytokines such as IL-2 o Once infection cleared and stimuli for lymphocyte activation disappear, many cells that had proliferated in response to antigen deprived of survival signals and begin to die by apoptosis o Response subsides within 1-2 weeks after infection eradicated

Numerous mechanisms ensure generation of useful T cell response, despite several obstacles o Naïve T cells have to find antigen; APCs capture antigen and concentrate it in specialized lymphoid organs and regions through which naïve T cells recirculate o Correct type of T lymphocytes must respond to antigens from extracellular and intracellular compartments; selectivity determined by specificity of CD4 and CD8 coreceptors for class II and class I

MHC molecules and by segregation of extracellular (vesicular – by class II MHC molecules) and intracellular (cytoplasmic – by class I MHC molecules) protein antigens for display o T cells must interact with antigen-bearing APCs long enough to be activated; accomplished by adhesion molecules that stabilize T cell binding to APCs

o T cells should respond to microbial antigens but not harmless proteins; preference maintained because

T cell activation requires costimulators induced on APCs by microbes o Antigen recognition by small number of T cells must lead to response large enough to be effective

 Accomplished by several amplification mechanisms induced by microbes and activated T cells themselves and lead to enhanced T cell activation